First enantioselective synthesis of exiguamide, a nitrogen-containing spirocyclic sesquiterpene isolated from the marine sponge Geodia exigua

Article abstract of DOI:10.1016/j.tet.2018.12.046

(+)-Exiguamide is a nitrogen-containing spirocyclic sesquiterpene isolated from the marine sponge Geodia exigua. This study aims to report the first synthesis of both enantiomers of exiguamide, featuring the stereoselective intramolecular cyclopropanation

Full text of DOI:10.1016/j.tet.2018.12.046

Accepted Manuscript
First enantioselective synthesis of exiguamide, a nitrogen-containing spirocyclic
sesquiterpene isolated from the marine sponge Geodia exigua
Shunsuke Konishi, Yuki Mitani, Naoki Mori, Hirosato Takikawa, Hidenori Watanabe
PII:
S0040-4020(18)31536-9
https://doi.org/10.1016/j.tet.2018.12.046
TET 30032
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 22 November 2018
Revised Date: 19 December 2018
Accepted Date: 21 December 2018
Please cite this article as: Konishi S, Mitani Y, Mori N, Takikawa H, Watanabe H, First enantioselective
synthesis of exiguamide, a nitrogen-containing spirocyclic sesquiterpene isolated from the marine
sponge Geodia exigua, Tetrahedron (2019), doi: https://doi.org/10.1016/j.tet.2018.12.046.
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First enantioselective synthesis of exiguamide,
a nitrogen-containing spirocyclic sesquiterpene
isolated from the marine sponge Geodia exigua
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Shunsuke Konishi, Yuki Mitani, Naoki Mori, Hirosato Takikawa, Hidenori Watanabe

1
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Tetrahedron
journal homepage: www.elsevier.com
First enantioselective synthesis of exiguamide, a nitrogen-containing spirocyclic
sesquiterpene isolated from the marine sponge Geodia exigua
Shunsuke Konishi a, b, Yuki Mitani a, Naoki Mori a, Hirosato Takikawa a, , Hidenori Watanabe a
a Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-
8657, Japan
b Technical Research Institute, R&D Center, T. Hasegawa Co., Ltd., 29-7 Kariyado, Nakahara-ku, Kawasaki, Kanagawa 211-0022, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
(+)-Exiguamide is a nitrogen-containing spirocyclic sesquiterpene isolated from the marine
sponge Geodia exigua. This study aims to report the first synthesis of both enantiomers of
exiguamide, featuring the stereoselective intramolecular cyclopropanation and stereoselective
homoconjugate addition of azide to cyclopropyl ketone as the key steps.
Available online
2009 Elsevier Ltd. All rights reserved
.
Keywords:
Exiguamide
Spirocyclic sesquiterpene
Enantioselective synthesis
Cyclopropanation
Homoconjugate addition
1. Introduction
In 2002, (+)-exiguamide (1) was isolated from the marine
sponge Geodia exigua by Ikegami et al. [1a] (Figure 1). This
nitrogen-containing spirocyclic sesquiterpene was reported to
inhibit the micromere formation of sea urchin embryos and
subsequent spicule formation at a quite low concentration. The
relative stereochemistry of (+)-1 was elucidated unambiguously
using X-ray crystallographic analysis, and its absolute
configuration was determined as 5S,6R,7S,10S by applying the
modified Mosher’s method to the amine derived from (+)-1 [1b].
There exist a certain number of structurally related marine
natural products as follows: (+)-exicarbamate (2) and (−)-
exigurin (3) isolated from G. exigua [1b]; (−)-10-epi-axisonitrile-
3 (4) isolated from Phyllidia pustulosa [2]; and (−)-axamide-3 (5)
and (+)-axisonitrile-3 (6) isolated from Axinella cannabina [3,4].
These compounds possess four contiguous stereogenic centers on
the spiro[4.5]decane skeleton. Although the enantioselective
synthesis of 5 and 6 has been reported [5], other four compounds
(1–4) with exiguamide-type stereochemistry have not been
synthesized yet. Inspired by the unique structure and interesting
biological profile of 1, we initiated our studies toward the
enantioselective synthesis of 1. Herein, we report the first
synthesis of both enantiomers of 1.
H
N
H
N
H
N
1
OMe
OMe
H
N
7
6
5
O
O
O
O
10
2
(+)-Exiguamide (1)
(+)-Exicarbamate (2)
(–)-Exigurin (3)
H
N
NC
H
NC
O
(+)-Axisonitrile-3 (6)
(–)-10-epi-Axisonitrile-3 (4) (–)-Axamide-3 (5)
Figure 1. Structures of (+)-exiguamide (1) and related marine
natural products.
2. Results and Discussion
Our synthetic plan for (+)-1 is shown in Scheme 1. We
anticipated that the synthesis of 1 would be achieved by Negishi
coupling of 7 followed by reduction of azide and sulfonyl groups.
The enol triflate 7 would be obtained from the tricyclic key
intermediate 8 by stereoselective homoconjugate 1,5-addition of
———
Corresponding author. Tel.: +81-3-5841-5119; fax: +81-3-5841-8019; e-mail: atakikawa@mail.ecc.u-tokyo.ac.jp

2
Tetrahedron
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azide group and regioselective enol triflation. In this sequence,
the sulfonyl group would play two important roles in accelerating
the homoconjugate addition and controlling the regioselectivity
in enolization. The cyclopropyl ketone 8 would be accessed by
the stereoselective intramolecular cyclopropanation of 9, which
would be efficiently prepared from the known optically active
ketone, (2S,5R)-carvomenthone [(+)-10] [6].
As shown in Scheme 2, our synthesis commenced with the
enol triflation [7] of (2S,5R)-carvomenthone [(+)-10] that was
prepared from (−)-(R)-carvone by hydrogenation and
chromatographic purification [6]. The enol triflate (−)-11 was
subjected to Heck reaction with methyl acrylate to give (+)-12 in
excellent yield. The diimide reduction of the ester (+)-12 (98%)
followed by condensation with the lithium salt of methyl phenyl
sulfone gave the β-ketosulfone (−)-14. The diazo-transfer
reaction of (−)-14 with p-TsN3 was executed to afford the
N3
homoconjugate
H
addition
SO2Ph
OTf
SO2Ph
O
corresponding
α-diazo-β-ketosulfone
(−)-9.
Subsequent
intramolecular cyclopropanation of (−)-9 was successfully
catalyzed by (CuOTf)2·C6H6 to afford the key intermediate (−)-8
as a single diastereomer (49% in three steps).
(+)-1
8
7
With the key intermediate (−)-8 in hand, attention was turned
to the homoconjugate 1,5-addition of azide to (−)-8.
Cyclopropanes with electron-withdrawing substituent are known
to undergo nucleophilic ring-opening in 1,5-addition manner [8].
Especially, doubly activated cyclopropanes with geminal two
electron-withdrawing substituents are preferable substrates for
homoconjugate addition, and this type of reaction is known to be
SO2Ph
cyclopropanation
N2
O
O
(+)-(2S,5R)-10
9
Scheme 1. Synthetic plan for (+)-1.
Scheme 2. Synthesis of (+)- and (−)-1.

3
accelerated with Lewis acid [9]. Thus, we chose Mg(OTf)2 as the
activator for conversion of 8 into 7. As a result, the
homoconjugate addition of azide to (−)-8 proceeded in the
presence of Mg(OTf)2 in DMPU to afford (+)-7 as a single
diastereomer in 70% yield [10]. The relative stereochemistry of
(+)-7 was confirmed based on NOE experiments as depicted in
Scheme 2. It is worth noting that the orientation of SO2Ph group
at C-1 was not clarified by NOE studies, but it was estimated to
be β based on thermodynamic stability [11].
raised at 0.7 °C/min. Mass spectra were recorded on JEOL JMS
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SX102 or JEOL JMS-T100GCV. Column chromatography was
performed on Merck silica gel 60 (0.060–0.200 mm), TLC was
carried out on Merck glass plates pre-coated with silica gel 60
F254 (0.25 mm).
4.2.
(3S,6S)-3-Isopropyl-6-methylcyclohex-1-enyl
trifluoromethanesulfonate [(−)-11]
LDA was prepared by adding n-BuLi (2.65 M in hexane;
28.8 mL, 76.3 mmol) to a solution of (i-Pr)2NH (10.7 mL, 76.3
mmol) in THF (150 mL) at −78 °C. The solution was stirred for
30 min at 0 °C and then cooled again to −78 °C. To the LDA
solution was added a solution of (2S,5R)-carvomenthone [(+)-10]
(9.69 g, 63.6 mmol, 98.0% ee) in THF (20 mL). After stirring for
1 h at −78 °C, PhNTf2 (25.0 g, 70.0 mmol) was added to the
mixture at −78 °C, and stirring was continued at −40 °C for 25 h.
The reaction mixture was poured into sat. aq. NH4Cl and
extracted with hexane. The organic phase was washed with brine,
dried over MgSO4 and concentrated in vacuo. The residue was
chromatographed over silica gel. Elution with hexane-EtOAc
(50:1) gave (−)-11 (17.4 g, 60.7 mmol, colorless oil, 95.4%).
After converting (+)-7 into the corresponding enol triflate (−)-
15 (97%), it was methylated by Negishi coupling under the
following conditions, i.e., Me2Zn, Pd(PPh3)4 in THF [12],
affording (+)-16 in 93% yield. Various reductive conditions were
screened for reductive removal of sulfonyl group and
transformation of azide into amine in one-pot. Although many
reducing reagents, e.g., Raney-Nickel, Na-Hg and sodium
naphthalenide, gave disappointing results, the desired reduction
was successfully performed by treatment with Mg powder in
MeOH to afford (+)-17 [13,14]. Finally, the obtained amine (+)-
17 was heated in ethyl formate under reflux to give (+)-
exiguamide (1) in 58% yield in two steps. The NMR data of
synthetic (+)-1 suggested that it was a mixture of two rotamers
25
[α]D −38.4 (c 1.0, CHCl3); IR (film): 2964, 2941, 2875, 1681,
1416, 1209, 1143, 885 cm−1; H NMR (400 MHz, CDCl3) δ 0.90
1
1
due to amide bond. H NMR and 13C NMR spectra of synthetic
(3H, d, J = 5.2 Hz), 0.92 (3H, d, J = 5.2 Hz), 1.14 (3H, d, J = 7.2
Hz), 1.39 (1H, m), 1.52–1.70 (3H, m), 1.84 (1H, ddt, J = 2.8, 6.0,
13.2 Hz), 2.16 (1H, m), 2.49 (1H, m), 5.64 (1H, d, J = 2.8 Hz);
13C NMR (100 MHz, CDCl3) δ 17.91, 19.39, 19.56, 20.23, 29.46,
31.69, 31.87, 41.95, 118.46 (q, 1JC–F= 318.5 Hz), 121.16, 153.73;
HR-FIMS m/z calcd for C11H17F3O3S [M]+: 286.0851, found
286.0861.
(+)-1 are in good accordance with those of the natural product
25
[1a]. The specific rotation value of the synthetic (+)-1, [α]D
=
+48.4 (c 0.08, CHCl3), showed the same sign to that of the
25
natural product, [α]D = +31.7 (c 0.08, CHCl3) [1a]. Similarly,
the synthesis of (−)-1 was also achieved by starting from (2R,5S)-
carvomenthone [(−)-10].
4.3.
(3R,6R)-3-Isopropyl-6-methylcyclohex-1-enyl
trifluoromethanesulfonate [(+)-11]
3. Conclusion
In the same manner as described above, (2R,5S)-
carvomenthone [(−)-10] (9.69 g, 63.6 mmol, 96.1% ee) afforded
(+)-11 (16.9 g, 59.1 mmol, 92.9%) as a colorless oil. [α]D29 +35.5
(c 1.0, CHCl3); HR-FIMS m/z calcd for C11H17F3O3S [M]+:
286.0851, found 286.0838. All other data were identical with
those of (−)-11.
In summary, we achieved the first synthesis of (+)-exiguamide
(1) using (2S,5R)-carvomenthone (10) as a chiral starting
material. The overall yield was 15% in 11 steps. For the
formation of the spirocyclic carbon framework, the
diastereoselective intramolecular cyclopropanation and the
following homoconjugate addition of azide were featured as the
key steps. The synthesis of (−)-1 was also achieved by starting
from (2R,5S)-10. Biological evaluation of both enantiomers of 1
and the synthesis of exiguamide analogs are currently under
investigation.
4.4. Methyl (E)-3-[(3′S,6′S)-3′-isopropyl-6′-methylcyclohex-1′-
enyl]prop-2-enoate [(+)-12]
To a solution of (−)-11 (16.9 g, 58.9 mmol) and KOAc (23.1
g, 235 mmol) in DMF (88 mL) was successively added methyl
acrylate (15.9 mL, 177 mmol) and Pd(OAc)2 (661 mg, 2.94
mmol) at room temperature, and stirring was continued at 70 °C
for 8 h. The reaction mixture was poured into ice-cooled water
and extracted with ether. The organic phase was washed with
brine, dried over MgSO4 and concentrated in vacuo. The residue
was chromatographed over silica gel. Elution with hexane-EtOAc
(20:1) gave (+)-12 (12.1 g, 54.4 mmol, slightly yellow oil,
92.5%). [α]D31 +3.42 (c 1.0, CHCl3); IR (film): 2958, 2871, 1721,
1624, 1285, 1166 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.88 (3H,
d, J = 6.8 Hz), 0.91 (3H, d, J = 6.8 Hz), 1.06 (3H, d, J = 7.2 Hz),
1.43 (1H, ddt, J = 4.0, 10.4, 12.8 Hz), 1.56 (1H, dt, J = 16.0, 3.2
Hz), 1.60–1.72 (3H, m), 2.13 (1H, m), 2.52 (1H, m), 3.74 (3H, s),
5.82 (1H, d, J = 16.0 Hz), 5.97 (1H, d, J = 2.4 Hz), 7.22 (1H, d, J
= 16.0 Hz); 13C NMR (100 MHz, CDCl3) δ 19.03, 19.54, 19.56,
27.47, 29.34 (×2), 31.94, 43.44, 51.41, 114.27, 140.33, 142.36,
147.96, 168.17; HR-FIMS m/z calcd for C14H22O2 [M]+:
222.1620, found 222.1618.
4. Experimental section
4.1. General
All air- and/or water-sensitive reactions were carried out
under Ar atmosphere in dry solvents. Solvents were dried as
follows; THF over sodium-benzophenone, CH2Cl2 over P2O5. All
melting points (mps) were uncorrected. Melting points were
recorded on a Yanaco Melting Point Apparatus. IR spectra were
1
measured with a Jasco FT/IR-230 spectrophotometer. H NMR
(400 MHz) and 13C NMR (100 MHz) data were recorded by
JEOL ECS400. Chemical shifts (δ) were referenced to the
residual solvent peak as the internal standard (CDCl3: δH = 7.26,
δC = 77.0; CD3OD: δH = 3.30, δC = 49.0; DMSO-d6: δH = 2.49, δC
= 39.5). Optical rotations were measured on a Jasco P-1030
polarimeter. The enantiomeric purities of 10 were determined by
gas chromatography using a chiral separative column: 50% (w/w)
2,3-MOM-6-TBDMS-β-CD in OV-1701 (30 m, ID 0.25 mm,
film 0.25 µm) [15]. The carrier gas was Helium with a flow rate
of 0.7 mL/min. Injector and detector temperatures were 230 °C
and 250 °C, respectively. The oven temperature was 40–180 °C,
4.5. Methyl (E)-3-[(3′R,6′R)-3′-isopropyl-6′-methylcyclohex-
1′-enyl]prop-2-enoate [(−)-12]
In the same manner as described above, (+)-11 (16.3 g, 57.0
mmol) afforded (−)-12 (11.8 g, 52.9 mmol, 92.8%) as a slightly

4
Tetrahedron
yellow oil. [α]D31 −6.54 (c 1.0, CHCl3); HR-FIMS m/z calcd for
4.10. 1-Diazo-4-[(3′S,6′S)-3′-isopropyl-6′-methylcyclohex-1′-
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C14H22O2 [M]+: 222.1620, found 222.1626. All other data were
enyl]-1-(phenylsulfonyl)butan-2-one [(−)-9]
identical with those of (+)-12.
To a solution of the crude (−)-14 in CH3CN (150 mL) were
successively added Et3N (10.5 mL, 75.3 mmol) and a solution of
p-TsN3 (7.39 g, 37.5 mmol) in CH3CN (15 mL) at 0 °C. After
stirring at room temperature for 15 h, the reaction mixture was
4.6. Methyl 3-[(3′S,6′S)-3′-isopropyl-6′-methylcyclohex-1′-
enyl]propanoate [(−)-13]
To a suspension of (+)-12 (12.1 g, 54.4 mmol) in THF (50
mL) and water (50 mL) were successively added NaOAc (20.1 g,
245 mmol) and p-TsNHNH2 (30.4 g, 163 mmol) at room
temperature, and the mixture was heated under reflux for 12 h.
The reaction mixture was poured into water and extracted with
hexane. The organic phase was washed with brine, dried over
MgSO4 and concentrated in vacuo. The residue was
chromatographed over silica gel. Elution with hexane-EtOAc
(10:1) gave (−)-13 (12.0 g, 53.3 mmol, colorless oil, 97.9%).
[α]D29 −16.4 (c 1.0, CHCl3); IR (film): 2957, 2932, 2870, 1743,
1436, 1165 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.83 (3H, d, J =
6.8 Hz), 0.86 (3H, d, J = 6.8 Hz), 1.00 (3H, d, J = 7.2 Hz), 1.34
(1H, m), 1.42–1.68 (4H, m), 1.88 (1H, m), 2.06 (1H, m), 2.20–
2.50 (4H, m), 3.66 (3H, s), 5.24 (1H, br s); 13C NMR (100 MHz,
CDCl3) δ 19.11, 19.55, 19.65, 20.36, 30.02, 30.40, 31.34, 32.17,
32.95, 42.12, 51.49, 124.93, 140.87, 174.11; HR-FIMS m/z calcd
for C14H24O2 [M]+: 224.1776, found 224.1788.
poured into 2
M aq. KOH and extracted with ether. The organic
phase was washed with dil. HCl and sat. aq. NaHCO3, dried over
MgSO4 and concentrated in vacuo. The residue was filtered
through silica gel, and the filtrate was concentrated in vacuo to
afford the crude (−)-9. A small amount of the crude (−)-9 was
purified by column chromatography on silica gel (toluene as
eluent) to give an analytical sample as a yellow viscous oil.
26
[α]D −14.0 (c 1.0, CHCl3); IR (film): 3064, 2957, 2932, 2869,
2108, 1667, 1447, 1341, 1155 cm−1; 1H NMR (400 MHz, CDCl3)
δ 0.80 (3H, d, J = 6.8 Hz), 0.84 (3H, d, J = 6.8 Hz), 0.92 (3H, d,
J = 6.8 Hz), 1.28 (1H, m), 1.40–1.60 (4H, m), 1.82 (1H, m), 1.93
(1H, m), 2.03–2.27 (2H, m), 2.61 (1H, ddd, J = 6.8, 8.4, 24.8
Hz), 2.65 (1H, ddd, J = 6.8, 8.4, 24.8 Hz), 5.10 (1H, br s), 7.57
(2H, t, J = 7.6 Hz), 7.67 (1H, t, J = 7.6 Hz), 7.98 (2H, d, J = 7.6
Hz); 13C NMR (100 MHz, CDCl3) δ 19.01, 19.46, 19.64, 20.14,
29.06, 29.89, 31.33, 32.05, 37.97, 42.01, 125.44, 127.33, 129.41,
134.10, 140.32, 141.92, 188.21; HR-ESIMS m/z calcd for
C20H26N2NaO3S [M+Na]+: 397.1562, found 397.1551.
4.7. Methyl 3-[(3′R,6′R)-3′-isopropyl-6′-methylcyclohex-1′-
enyl]propanoate [(+)-13]
4.11. 1-Diazo-4-[(3′R,6′R)-3′-isopropyl-6′-methylcyclohex-1′-
enyl]-1-(phenylsulfonyl)butan-2-one [(+)-9]
In the same manner as described above, (−)-12 (11.1 g, 50.0
mmol) afforded (+)-13 (11.0 g, 48.9 mmol, 97.8%) as a colorless
In the same manner as described above, the crude (+)-14
29
oil. [α]D +19.9 (c 1.0, CHCl3); HR-FIMS m/z calcd for
27
afforded crude (+)-9. [α]D +13.6 (c 1.0, CHCl3); HR-ESIMS
C14H24O2 [M]+: 224.1776, found 224.1787. All other data were
m/z calcd for C20H26N2NaO3S [M+Na]+: 397.1562, found
397.1570. All other data were identical with those of (−)-9.
identical with those of (−)-13.
4.8.
4-[(3′S,6′S)-3′-Isopropyl-6′-methylcyclohex-1′-enyl]-1-
4.12.
(1R,5S,6S,7S,10S)-7-Isopropyl-10-methyl-5-
(phenylsulfonyl)butan-2-one [(−)-14]
phenylsulfonyltricyclo[4.4.0.01,5]decan-4-one [(−)-8]
To a solution of MeSO2Ph (8.20 g, 52.5 mmol) in THF (250
mL) was added n-BuLi (2.65 M in hexane, 19.3 mL, 51.3 mmol)
at 0 °C. After stirring for 30 min, a solution of (−)-13 (5.61 g,
25.0 mmol) in THF (20 mL) was added at 0 °C and stirring was
continued at 0 °C for 2 h. The reaction mixture was poured into a
sat. aq. NH4Cl and extracted with EtOAc. The organic phase was
washed with brine, dried over MgSO4 and concentrated in vacuo.
The residue was used in the next step without purification. A
small amount of the crude (−)-14 was purified by column
chromatography on silica gel (hexane-EtOAc = 4:1) to give an
analytical sample as a slightly yellow viscous oil. [α]D27 −12.7 (c
1.0, CHCl3); IR (film): 3064, 2957, 2931, 2869, 1720, 1585,
1447, 1322, 1154 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.83 (3H,
d, J = 6.8 Hz), 0.86 (3H, d, J = 6.8 Hz), 0.98 (3H, d, J = 7.6 Hz),
1.31 (1H, m), 1.43–1.64 (4H, m), 1.87 (1H, m), 2.04 (1H, m),
2.16–2.31 (2H, m), 2.76 (1H, ddd, J = 6.4, 8.8 17.6 Hz), 2.84
(1H, ddd, J = 6.4, 8.8 17.6 Hz), 4.16 (2H, s), 5.20 (1H, s), 7.58
(2H, t, J = 7.6 Hz), 7.68 (1H, t, J = 7.6 Hz), 7.89 (2H, d, J = 7.6
Hz); 13C NMR (100 MHz, CDCl3) δ 19.11, 19.54, 19.73, 20.29,
28.77, 29.97, 31.31, 32.14, 42.14, 43.11, 66.79, 125.52, 128.29,
129.31, 134.27, 138.64, 140.36, 198.09; HR-ESIMS m/z calcd
for C20H28NaO3S [M+Na]+: 371.1657, found 371.1672.
To a solution of the crude (−)-9 in CH2Cl2 (250 mL) was
added (CuOTf)2·C6H6 (315 mg, 0.63 mmol) at 0 °C. After
stirring at 0 °C for 6 h, the same amount of (CuOTf)2·C6H6 was
added. The reaction mixture was stirred for 15 h at 0 °C and
concentrated in vacuo. The residue was chromatographed over
silica gel. Elution with hexane-EtOAc (5:1) gave (−)-8 (4.27 g,
12.3 mmol, yellow solid, 49.3% in 3 steps). An analytical sample
was obtained by recrystallization from CH2Cl2/hexane as
28
colorless crystals. mp 131 °C; [α]D −57.1 (c 1.0, CHCl3); IR
(film): 3067, 3022, 2959, 2873, 1730, 1585, 1466, 1447, 1308,
1
1149 cm−1; H NMR (400 MHz, CDCl3) δ 0.95 (3H, d, J = 6.8
Hz), 1.02 (3H, d, J = 6.8 Hz), 1.14 (3H, d, J = 6.8 Hz), 1.18 (1H,
m), 1.35 (1H, m), 1.50 (1H, dq, J = 13.6, 6.8 Hz), 1.57 (1H, d, J
= 8.0 Hz), 1.81–1.96 (3H, m), 2.00–2.20 (3H, m), 2.37 (1H, ddt,
J = 4.8, 12.8, 7.2 Hz), 2.82 (1H, tt, J = 6.8, 11.2 Hz), 7.51 (2H, t,
J = 7.6 Hz), 7.60 (1H, t, J = 7.6 Hz), 8.00 (2H, d, J = 7.6 Hz); 13C
NMR (100 MHz, CDCl3) δ 18.30, 19.50, 20.57, 22.37, 24.29,
29.03, 32.42, 33.77, 34.78, 39.41, 46.15, 58.16, 128.51, 128.59,
133.40, 141.40, 205.61; HR-ESIMS m/z calcd for C20H26NaO3S
[M+Na]+: 369.1500, found 369.1508.
4.13.
(1S,5R,6R,7R,10R)-7-Isopropyl-10-methyl-5-
phenylsulfonyltricyclo[4.4.0.01,5]decan-4-one [(+)-8]
4.9. 4-[(3′R,6′R)-3′-Isopropyl-6′-methylcyclohex-1′-enyl]-1-
(phenylsulfonyl)butan-2-one [(+)-14]
In the same manner as described above, the crude (+)-9
afforded (+)-8 (4.83 g, 13.9 mmol, 39.8% in 3 steps) as colorless
crystals. mp 131 °C; [α]D25 +57.1 (c 1.0, CHCl3); HR-ESIMS m/z
calcd for C20H26NaO3S [M+Na]+: 369.1500, found 369.1504. All
other data were identical with those of (−)-8.
In the same manner as described above, (+)-13 (7.85 g, 35.0
28
mmol) afforded the crude (+)-14. [α]D +12.2 (c 1.0, CHCl3);
HR-ESIMS m/z calcd for C20H28NaO3S [M+Na]+: 371.1657,
found 371.1648. All other data were identical with those of (−)-
14.
4.14.
(1R,5R,6R,7S,10S)-6-Azido-7-isopropyl-10-methyl-1-
phenylsulfonylspiro[4.5]decan-2-one [(+)-7]

5
A mixture of (−)-8 (4.17 g, 12.0 mmol), NaN3 (3.91 g, 60
4.18. (5R,6R,7S,10S)-6-Azido-7-isopropyl-2,10-dimethyl-1-
phenylsulfonylspiro[4.5]dec-1-ene [(+)-16]
ACCEPTED MANUSCRIPT
mmol) and Mg(OTf)2 (3.90 g, 12.1 mmol) in N,N′-
dimethylpropyleneurea (120 mL) was heated at 80 °C for 20 h.
The reaction mixture was poured into sat. aq. NaHCO3 and
extracted with ether. The organic phase was washed with water
and brine, dried over MgSO4 and concentrated in vacuo. The
residue was chromatographed over silica gel. Elution with
hexane-EtOAc (8:1) gave (+)-7 (3.30 g, 8.47 mmol, colorless
To a solution of (−)-15 (166 mg, 0.318 mmol) in THF (8 mL)
was added Pd(PPh3)4 (36.7 mg, 0.0318 mmol) at 0 °C. After
stirring for 10 min, Me2Zn (2.0 M in toluene, 477 µl, 0.954
mmol) was added to the solution at 0 °C, and stirring was
continued at room temperature for 10 h. The reaction mixture
was poured into dil. HCl and extracted with EtOAc. The organic
phase was washed with sat. aq. NaHCO3, dried over MgSO4 and
concentrated in vacuo. The residue was chromatographed over
silica gel. Elution with hexane-EtOAc (10:1) gave (+)-16 (115
25
solid, 70.4%). mp 158–159 °C; [α]D +52.8 (c 1.0, CHCl3); IR
(film): 3066, 2962, 2875, 2102, 1749, 1585, 1448, 1310, 1155
1
cm−1; H NMR (400 MHz, CDCl3) δ 1.03 (3H, d, J = 6.4 Hz),
1.13 (3H, d, J = 6.4 Hz), 1.17 (3H, s), 1.18 (1H, m), 1.35 (1H, dq,
J = 4.4, 120 Hz), 1.47–1.62 (3H, m), 1.66–1.77 (2H, m), 2.25
(1H, dt, J = 19.2, 9.6 Hz), 2.53 (1H, dd, J = 8.4, 12.8 Hz), 2.63
(1H, dd, J = 9.6, 19.2 Hz), 2.73 (1H, m), 3.60 (1H, s), 4.80 (1H,
s), 7.57 (2H, t, J = 7.6 Hz), 7.69 (1H, dt, J = 1.2, 7.6 Hz), 7.78
(2H, dd, J = 1.2, 7.6 Hz); 13C NMR (100 MHz, CDCl3) δ 16.04,
18.89, 20.08, 20.88, 28.94, 28.98, 30.18, 34.00, 34.13, 45.85,
54.42, 66.36, 78.01, 128.85, 128.99, 134.27, 138.28, 207.51; HR-
ESIMS m/z calcd for C20H27N3NaO3S [M+Na]+: 412.1671, found
412.1653.
23
mg, 0.296 mmol, colorless solid, 93.1%). mp 124–125 °C; [α]D
+29.2 (c 1.0, CHCl3); IR (film): 2960, 2930, 2870, 2097, 1616,
1461, 1301, 1143, 1084 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.73
(3H, d, J = 6.8 Hz), 0.90 (3H, d, J = 6.4 Hz), 1.17 (3H, d, J = 6.4
Hz), 1.18 (1H, m), 1.39 (1H, m), 1.48 (1H, tt, J = 3.6, 13.6 Hz),
1.72–1.78 (2H, m), 1.82 (1H, m), 1.92–2.00 (2H, m), 2.09 (3H,
s), 2.31–2.48 (3H, m), 4.76 (1H, d, J = 4.8 Hz), 7.54–7.60 (3H,
m), 7.94 (2H, dd, J = 1.2, 7.6 Hz); 13C NMR (100 MHz, CDCl3)
δ 16.13, 16.88, 22.35, 23.02, 25.10, 26.09, 26.59, 27.59, 38.25,
40.11, 43.88, 64.15, 67.85, 126.85, 128.95, 132.79, 137.57,
143.18, 158.44; HR-ESIMS m/z calcd for C21H29N3NaO2S
[M+Na]+: 410.1878, found 410.1870.
4.15.
(1S,5S,6S,7R,10R)-6-Azido-7-isopropyl-10-methyl-1-
phenylsulfonylspiro[4.5]decan-2-one [(−)-7]
In the same manner as described above, (+)-8 (3.98 g, 11.5
mmol) afforded (−)-7 (2.94 g, 7.56 mmol, 65.8%) as a colorless
4.19.
(5S,6S,7R,10R)-6-Azido-7-isopropyl-2,10-dimethyl-1-
phenylsulfonylspiro[4.5]dec-1-ene [(−)-16]
24
solid. mp 157–158 °C; [α]D −51.8 (c 1.0, CHCl3); HR-ESIMS
In the same manner as described above, (+)-15 (1.49 g, 2.85
mmol) afforded (−)-16 (1.05 g, 2.72 mmol, 95.4%) as a colorless
m/z calcd for C20H27N3NaO3S [M+Na]+: 412.1671, found
412.1664. All other data were identical with those of (+)-7.
24
solid. mp 122 °C; [α]D −30.9 (c 1.0, CHCl3); HR-ESIMS m/z
4.16.
(5R,6R,7S,10S)-6-Azido-7-isopropyl-10-methyl-1-
calcd for C21H29N3NaO2S [M+Na]+: 410.1878, found 410.1870.
phenylsulfonylspiro[4.5]dec-1-en-2-yl trifluoromethanesulfonate
All other data were identical with those of (+)-16.
[(−)-15]
4.20. (5S,6R,7S,10S)-7-Isopropyl-2,10-dimethylspiro[4.5]dec-
To a solution of (+)-7 (390 mg, 1.00 mmol) in CH2Cl2 (5 mL)
were successively added DBU (275 µl, 1.84 mmol) and Tf2O
(252 µl, 1.50 mmol) at 0 °C and stirring was continued for 20
min. The reaction mixture was poured into sat. aq. NaHCO3 and
extracted with CH2Cl2. The organic phase was dried over MgSO4
and concentrated in vacuo. The residue was chromatographed
over silica gel. Elution with hexane-EtOAc (10:1) gave (−)-15
(505 mg, 0.968 mmol, colorless solid, 96.8%). mp 116–119 °C;
1-en-6-ylamine [(+)-17]
To a solution of (+)-16 (77.9 mg, 0.201 mmol) in MeOH (2
mL) was added Mg powder (243 mg, 10.0 mmol) and the
mixture was heated under reflux. After stirring for 1.5 h, the
mixture was diluted with EtOAc, and the suspension was filtered
through a pad of Celite. The filtrate was concentrated in vacuo to
afford the crude (+)-17, which was used in the next step without
further purification. A small amount of the crude (+)-17 was
purified by column chromatography on silica gel (CH2Cl2-MeOH
23
[α]D −20.8 (c 1.0, CHCl3); IR (film): 3069, 2965, 2934, 2872,
2100, 1638, 1585, 1326, 1150 cm−1; 1H NMR (400 MHz, CDCl3)
δ 0.91 (3H, d, J = 2.8 Hz), 0.93 (3H, d, J = 2.8 Hz), 1.19 (1H, m),
1.20 (3H, d, J = 6.0 Hz), 1.46 (1H, m), 1.52 (1H, tt, J = 3.2, 13.6
Hz), 1.74–1.83 (2H, m), 1.87 (1H, ddd, J = 2.4, 9.6, 12.8 Hz),
2.01 (1H, m), 2.10 (1H, ddd, J = 8.4, 10.4, 12.8 Hz), 2.47 (1H,
ddt, J = 4.4, 18.8, 11.2 Hz), 2.62 (1H, ddd, J = 2.4, 10.8, 18.0
Hz), 2.70 (1H, dt, J = 8.4, 18.0 Hz), 4.79 (1H, d, J = 4.4 Hz),
7.58–7.68 (3H, m), 7.99 (2H, dd, J = 1.6, 6.8 Hz); 13C NMR (100
MHz, CDCl3) δ 15.86, 22.27, 23.04, 23.40, 25.61, 26.68, 27.47,
27
= 5:1) to give an analytical sample as a slightly yellow oil. [α]D
+33.6 (c 1.0, CHCl3); IR (film): 3043, 2957, 2928, 2869, 1614,
1456, 1375, 993 cm−1; 1H NMR (400 MHz, CD3OD) δ 0.89 (3H,
d, J = 6.4 Hz), 0.94 (3H, d, J = 6.4 Hz), 1.04 (3H, d, J = 7.6 Hz),
1.25 (1H, m), 1.41–1.58 (5H, m), 1.69 (3H, s), 1.70–1.85 (2H,
m), 2.01 (1H, ddd, J = 4.8, 8.0, 12.8 Hz), 2.18 (1H, m), 2.28 (1H,
m), 2.79 (1H, d, J = 3.2 Hz), 5.49 (1H, br s); 13C NMR (100
MHz, CD3OD) δ 16.91, 17.54, 21.03, 21.56, 22.05, 29.54, 30.43,
33.54, 36.39, 38.36, 46.76, 57.42, 58.16, 133.71, 140.66; HR-
FIMS m/z calcd for C15H27N [M]+: 221.2144, found 221.2155.
1
31.18, 38.11, 43.71, 60.00, 67.10, 118.16 (q, JC–F= 319.4 Hz),
127.90, 129.14, 133.94, 133.98, 140.99, 155.18; HR-ESIMS m/z
calcd for C21H26F3N3NaO5S2 [M+Na]+: 544.1164, found
544.1155.
4.21.
(5R,6S,7R,10R)-7-Isopropyl-2,10-
dimethylspiro[4.5]dec-1-en-6-ylamine [(−)-17]
4.17.
(5S,6S,7R,10R)-6-Azido-7-isopropyl-10-methyl-1-
In the same manner as described above, (−)-16 (194 mg, 0.503
23
phenylsulfonylspiro[4.5]dec-1-en-2-yl trifluoromethanesulfonate
[(+)-15]
mmol) afforded the crude (−)-17. [α]D −30.7 (c 1.0, CHCl3);
HR-FIMS m/z calcd for C15H27N [M]+: 221.2144, found
221.2149. All other data were identical with those of (+)-17.
In the same manner as described above, (−)-7 (1.81 g, 4.64
mmol) afforded (+)-15 (2.31 g, 4.43 mmol, 95.4%) as a colorless
4.22. (+)-Exiguamide [(+)-1]
26
solid. mp 116–118 °C; [α]D +19.4 (c 1.0, CHCl3); HR-ESIMS
m/z calcd for C21H26F3N3NaO5S2 [M+Na]+: 544.1164, found
544.1154. All other data were identical with those of (−)-15.
A solution of the crude (+)-17 in HCOOEt (3 mL) was heated
under reflux for 6 h. The reaction mixture was chromatographed
over silica gel. Elution with hexane-EtOAc (5:1) gave (+)-1 (29.0
mg, 0.116 mmol, colorless solid, 57.9% in 2 steps). mp 140–141

6
Tetrahedron
ACCEPTED MANUSCRIPT
25
12. (a) N. Arai, H. Ui, I. Kuwajima, Synlett (2005) 1692–1694; (b)
°C (recrystallized from MeOH/H2O); [α]D +48.4 (c 0.08,
CHCl3), [α]D25 +46.4 (c 1.0, CHCl3); IR (film): 3310, 3042, 2959,
L.Z. Liu, J.C. Han, G.Z. Yue, C.C. Li, Z. Yang, J. Am. Chem.
Soc. 132 (2010) 13608–13609.
2928, 2870, 1654, 1530, 1456, 1380, 756 cm−1; H NMR (400
1
13. For reductive removal of sulfonyl group with Mg powder, see: (a)
Y. Kazuta, A. Matsuda, S. Shuto, J. Org. Chem. 67 (2002) 1669–
1677; (b) A.G. Neo, C. López, V. Romero, B. Antelo, J.
Delamano, A. Pérez, D. Fernández, J.F. Almeida, L. Castedo, G.
Tojo, J. Org. Chem. 75 (2010) 6764–6770.
14. For reduction of azide into amine with Mg powder, see: (a) J.
Stichler-Bonaparte, B. Bernet, A. Vasella, Helv. Chim. Acta 85
(2002) 2235–2257; b) S. Hanessian, B. Deschênes-Simard, D.
Simard, Tetrahedron 65 (2009) 6656–6669.
MHz, DMSO-d6) δ 0.66 (3H, d, J = 6.4 Hz), 0.85 (3H, d, J = 6.4
Hz), 0.93 (3H, d, J = 7.6 Hz), 1.09 (1H, ddt, J = 9.6, 12.8, 3.2
Hz), 1.25–1.49 (5H, m), 1.55 (1H, dd, J = 3.2, 13.2 Hz), 1.67
(3H, s), 1.72 (1H, dt, J = 14.0, 4.0 Hz), 1.78 (1H, ddd, J = 2.0,
8.0, 12.4 Hz), 1.98 (1H, dd, J = 8.0, 15.6 Hz), 2.33 (1H, dt, J =
15.6, 8.0 Hz), 3.80 (1H, dd, J = 3.2, 10.4 Hz), 5.57 (1H, br s),
7.64 (1H, d, J = 10.4 Hz), 8.07 (1H, d, J = 1.6 Hz); 13C NMR
(100 MHz, DMSO-d6) δ 15.92, 16.90, 19.47, 20.43, 21.16, 29.09,
29.48, 33.88, 34.73, 36.42, 43.40, 50.35, 56.21, 131.83, 139.39,
161.27; HR-ESIMS m/z calcd for C16H27NNaO [M+Na]+:
272.1985, found 272.1973.
15. E. Takahisa, K-H. Engel, J. Chromatogr., A 1076 (2005) 148-154.
4.23. (−)-Exiguamide [(−)-1]
In the same manner as described above, the crude (−)-17
afforded (−)-1 (71.0 mg, 0.285 mmol, 57.0% in 2 steps) as a
colorless solid. mp 140–141 °C (recrystallized from
28
25
MeOH/H2O); [α]D −47.9 (c 0.08, CHCl3), [α]D −45.1 (c 1.0,
CHCl3); HR-ESIMS m/z calcd for C16H27NNaO [M+Na]+:
272.1985, found 272.1979. All other data were identical with
those of (+)-1.
Acknowledgments
Our thanks are due to T. Hasegawa Co., Ltd. for financial
support. We also thank Professor Emeritus Susumu Ikegami
(Hiroshima University) and Professor Shinji Ohta (Hiroshima
University) for a kind gift of the spectral charts of natural
exiguamide.
Appendix A. Supplementary data
Supplementary data related to this article can be found at ~.
References and notes
1. (a) M.M. Uy, S. Ohta, M. Yanai, E. Ohta, T. Hirata, S. Ikegami,
Bioorg. Med. Chem. Lett. 12 (2002) 3037–3039; (b) M.M. Uy, S.
Ohta, M. Yanai, E. Ohta, T. Hirata, S. Ikegami, Tetrahedron 59
(2003) 731–736.
2. T. Okino, E. Yoshimura, H. Hirota, N. Fusetani, Tetrahedron 52
(1996) 9447–9454.
3. B.D. Blasio, E. Fattorusso, S. Magno, L. Mayol, C. Pedone, C.
Santacroce, D. Sica, Tetrahedron 32 (1976) 473–478.
4. (+)-5 and (−)-6 were isolated from Halichondria sp.: H. Prawat, C.
Mahidol, S. Wittayalai, P. Intachote, T. Kanchanapoom, S.
Ruchirawat, Tetrahedron 67 (2011) 5651–5655.
5. (a) D. Caine, H. Deutsch, J. Am. Chem. Soc. 100 (1978) 8030–
8031; (b) T. Tamura, A. Nakazaki, S. Kobayashi, Synlett. (2009)
2449–2452.
6. (a) R.G. Johnston, J. Read, J. Chem. Soc. (1935) 1138–1143; (b)
T. Hirata, K. Shimoda, D. Ohba, N. Furuya, S. Izumi,
Tetrahedron: Asymmetry 8 (1997) 2671–2673; (c) D.F. Schneider,
M.S. Viljoen, Tetrahedron 58 (2002) 5307–5315.
7. A. Fürstner, P. Hannen, Chem. Eur. J. 12 (2006) 3006–3019.
8. For reviews, see: S.J. Danishefsky, Acc. Chem. Res. 12 (1979)
66–72; (b) H.U. Reissig, R. Zimmer, Chem. Rev. 103 (2003)
1151–1196.
9. Examples of Lewis acid-promoted ring-opening of activated
cyclopropanes: (a) S. Tanimori, M. He, M. Nakayama, Synth.
Commun. 23 (1993) 2861–2868; (b) N.A. Swain, R.C.D. Brown,
G. Bruton, J. Org. Chem. 69 (2004) 122–129; (c) O. Lifchits, A.B.
Charette, Org. Lett. 10 (2008) 2809–2812; (d) P.M. Wright, A.G.
Myers, Tetrahedron 67 (2011) 9853–9869.
10. When using the compound without sulfonyl group as a substrate,
the homoconjugate addition of azide did not proceed at all.
11. On the basis of DFT calculations, β-isomer is considerably more
stable than α-isomer. The calculated most stable conformation of
7 can explain the observed NOE correlations precisely.

ACCEPTED MANUSCRIPT
Highlights：
The first synthesis of both enantiomers of exiguamide was achieved.
Exiguamide is a nitrogen-containing spirocyclic sesquiterpene isolated from Geodia exigua.
The intramolecular cyclopropanation and homoconjugate addition of azide were the key steps.